The kidney is a comparatively hostile microenvironment characterized by highsodium concentrations; however, lymphocytes infiltrate and survive therein in autoimmune diseases such as lupus. The effects of sodium-lymphocyte interactions on tissue injury in autoimmune diseases and the mechanisms used by infiltrating lymphocytes to survive the highsodium environment of the kidney are not known. Here, we show that kidneyinfiltrating B cells in lupus adapt to elevated sodium concentrations and that expression of sodium potassium adenosine triphosphatase (Na⁺-K⁺-ATPase) correlates with the ability of infiltrating cells to survive. Pharmacological inhibition of Na+-K+-ATPase and genetic knockout of Na⁺-K⁺-ATPase γ subunit resulted in reduced B cell infiltration into kidneys and amelioration of proteinuria. B cells in human lupus nephritis biopsies also had high expression of Na⁺-K⁺-ATPase. Our study reveals that kidney-infiltrating B cells in lupus initiate a tissue adaption program in response to sodium stress and identifies Na⁺-K⁺-ATPase as an organ-specific therapeutic target.